Nitric oxide (NO) signaling is essential for normal physiological function in the central nervous system (CNS) and is compromised in many disease states. NO can serve as a retrograde synaptic messenger, as an intracellular messenger, and as a lateral diffusible messenger in the CNS. NO plays a critical role in signal transduction cascades that are compromised in dementia, and thereby contribute to the symptoms of cognitive impairment that characterize Alzheimer's Disease (AD). NO activates soluble guanylyl cyclase (sGC) to release cyclic guanosine-2′:3′-monophosphate (cGMP). NO/cGMP signaling is important for modulating synaptic transmission and plasticity in brain regions, such as the hippocampus and cerebral cortex, which are critical for learning and memory (H. Son et al., Learn Mem 1998, 5, 231-245; and Y. F. Lu et al., J Neurosci 1999, 19, 10250-10261). Evidence exists that NO may positively impact learning, memory, and cognition through cGMP-dependent and independent pathways (T. M. Edwards et al., Neurobiol Learn Mem 2002, 77, 313-326).
Compounds that mimic the effects of NO, i.e., NO mimetics, bypass cholinergic receptor activation and are expected to provide multiple pathways of treating and circumventing dementia. The action of an appropriate nitrate in the hippocampus modulates signaling cascades, in part via MAPK/ERK (mitogen activated protein kinase-extracellular signal-regulated kinase) and CREB (cAMP responsive element binding protein), leading to amelioration of learning and memory pathways under pathophysiological conditions which might lead to neurodegeneration.
Nitrates are NO mimetics that can act as NO donors. In contrast to other NO donors, nitrates do not release high fluxes of NO, which is potentially harmful. Bioactivation and metabolism of nitrates is a variable that strongly influences activity and pharmaceutical use. Whereas the potent hypotensive effects of the organic nitrate vasodilator nitroglycerin may be deleterious in the treatment of depression and dementia, it is theorized herein, but not relied upon, that regulation of systemic versus central effects is required for development of new and useful therapeutic agents useful in the treatment of brain injuries, dementia, and neurological diseases.
Cerebral ischemia results in marked increases in the release of the excitatory amino acid glutamate in the affected brain region (Bullock et al., 1998; Huang et al., 1998; Yang et al., 1998). In both humans (Bullock et al., 1998) and experimental animals (Huang et al., 1998; Goda et al., 1998; Yang et al., 1998), the amount of glutamate released during ischemia is positively correlated with the extent of brain injury. In experimental animal models of cerebral ischemia, a decreased release of glutamate during ischemia (Goda et al., 1998) or a blockade of glutamate receptors with antagonists (Ibarrola et al., 1998; O'Neill et al., 1998; Umemura et al., 1997) significantly reduces the extent of brain injury. However, these interventions are only effective when administered prior to or during the ischemic insult. To be broadly useful, a therapeutic intervention preferably is effective when administered after a period of ischemia.
Reoxygenation and reperfusion after a period of ischemia contributes significantly to the development of brain injury. Oxygen radicals, especially superoxide and peroxynitrite, formed in the period after an ischemic event, may initiate processes, such as breakdown of membrane lipids (lipid peroxidation), that lead to loss of cell membrane integrity and inhibition of mitochondrial function (Macdonald and Stoodley, 1998; Gaetani et al, 1998). Oxidative stress may be a factor involved in initiation of apoptotic neuronal cell death (Tagami et al., 1998). In experimental animal models of ischemic brain injury, a cytokine attenuating anti-inflammatory compound has been found to reduce the extent of neuronal injury and cell death (Chan et al., 1998; Mizuno et al., 1998; Tagami et al., 1998). Neurodegeneration therefore is mitigated by inhibition of cytokine induced damage.
Clomethiazole (CMZ) is a sedative/hypnotic and anticonvulsant, currently in clinical use for anxiety in the elderly. Ample evidence supports the actions of CMZ as both GABAmimetic and anti-inflammatory. These properties together provide neuroprotection in animal models of ischemic stroke (A. N. Clarkson et. al., 2005, The FASEB Journal, 19, 1036-1038). In addition to acting as a GABAA potentiator, it has been proposed that CMZ also inhibits the p38 mitogen-activated protein kinase pathway (A. Simi et al., 2000, Journal of Cerebral Blood Flow & Metabolism, 20, 1077-1088) and decreases inducible nitric oxide synthase (iNOS) expression in cortical glial cells (M. J. Wilby et. al., 2004, CNS Drug Reviews, 10, 281-294). AR-A008055 was reported as a CMZ analog (R. M. Nelson et. al., 2001, Neuropharmacology, 41, 159-166).

GT-1061 incorporates the 5-methylthiazole (MZ) pharmacophore of CMZ and retains GABAA potentiating, as well as anticonvulsant, activity with attenuated sedative/hypnotic effects. In preclinical studies, GT-1061 reversed cognitive impairment in experimental models of dementia, and also significantly improved learning and memory in experimental animals in which the cholinergic systems of the basal forebrain had been lesioned (B. M. Bennett et al., Neuropsychopharmacology 2007, 32, 505-13; G. R. J. Thatcher et al., Curr Alzheimer. Res. 2006, 3, 237-45; G. R. J. Thatcher et al., J. Alzheimer's Dis. 2004, 6, S75-84.). The aliphatic nitrate group of GT-1061 provides nitric oxide (NO) mimetic activity via cGMP/ERK/CREB signal transduction enhancing synaptic plasticity and via brain-derived neurotrophic factor (BDNF) upregulation, thereby enhancing neuronal plasticity and neurogenesis. Evidence exists for attenuated NO/cGMP signaling and downregulated BDNF in Alzheimer's disease (AD) and other neurodegenerative diseases associated with aging. GT-1061 has completed Phase 1A clinical trials for AD.
The present invention therefore is directed to novel 4-methylthiazole compounds having neuroprotective and anti-neuroinflammatory properties, and that are useful in the methods of protecting brain tissue from injury and of ameliorating symptoms and pathologies associated with brain injuries.